Medicament Delivery Device

ABSTRACT

The present disclosure relates to a medicament delivery devicecomprising at least one microneedle for delivering a medicament to a patient, and a system configured to enhance the penetration of the medicament into skin of the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 16/472,263, filed on Jun. 21, 2019, which is the national stageentry of International Patent Application No. PCT/EP2017/084146, filedon Dec. 21, 2017, and claims priority to Application No. EP 16206617.9,filed on Dec. 23, 2016, the disclosures of which are incorporated hereinby reference.

TECHNICAL FIELD

The disclosure relates to a device for delivery of medicament to apatient.

BACKGROUND

A variety of diseases exists that require regular treatment by injectionof a medicament. Such injection can be performed by using hypodermicinjection devices, which are applied either by medical personnel or bypatients themselves. As an example, type-1 and type-2 diabetes can betreated by injection of insulin doses, for example once or several timesper day, using an insulin injection device. This type of devicestypically comprises a insulin pump connected to cannula or an hypodermicinjection needle through which the insulin can flow towards the skin ofthe patient.

SUMMARY

Some aspects relate to a medicament delivery device.

According to a further aspect, there is provided a medicament deliverydevice comprising at least one microneedle for delivering a medicamentto a patient; and a system configured to enhance the penetration of themedicament into the skin of the patient.

The system may comprise a first electrode, a second electrode, and apower supply connected to the first and second electrodes, the systembeing configured to generate an electric field between the first andsecond electrodes, the first and second electrodes being arranged suchthat, in use, the electric field generated between the first and secondelectrodes drives the medicament towards the skin of the patient.

The second electrode may be permeable such that, in use, medicamentdriven by the electric field flows through the second electrode towardsthe skin of the patient. The second electrode may comprise a perforatedplate.

The system may be configured to generate a pulsed electric field betweenthe first and second electrodes.

The system may comprise a heating element configured to heat the skin ofthe patient.

The heating element may be permeable such that, in use, medicament flowsthrough the heating element towards the skin of the patient. The heatingelement may comprise a perforated heating foil.

The system may comprise a heat controller for controlling the heatingelement.

The system may be configured to deliver a chemical penetration enhancerinto the skin of the patient.

The system may comprise a mechanism for mixing the chemical penetrationenhancer to the medicament prior to the medicament delivery into theskin of the patient.

The medicament delivery device may comprise a porous membrane arrangedadjacent to the at least one microneedle, and the porous membrane may beconfigured to retain the medicament.

The medicament delivery device may comprise a medicament pump mechanismfor pumping the medicament towards the at least one microneedle.

The medicament delivery device may comprise a reusable part and adisposable part, and the medicament pump mechanism may be located in thedisposable part. In an alternative embodiment, the medicament pumpmechanism may be located in the reusable part.

The medicament delivery device may comprise a plurality of microneedles.

The medicament delivery device may comprise a cartridge of medicament.

The medicament delivery device may be an insulin delivery device.

The medicament delivery device may be a wearable device. The medicamentdelivery device may comprise a bottom surface configured to removablyattach to the skin of the patient.

The medicament delivery device may comprise a controller for controllingthe medicament delivery to the patient.

The medicament delivery device may comprise a blood glucose sensorconfigured to send data relating to the blood glucose of the patient tothe controller so that the controller controls the insulin delivery tothe patient.

The medicament delivery device may comprise a wireless communicationunit configured to transmit and/or receive information to/from anotherdevice in a wireless fashion.

According to a further aspect there is provided a method of enhancingthe penetration of a medicament into a skin of the patient, comprisingusing a medicament delivery device comprising at least one microneedlefor delivering the medicament to a patient and a system configured toenhance the penetration of the medicament into the skin of the patient.

The system may comprise a first electrode, a second electrode, and apower supply connected to the first and second electrodes, and themethod may comprise generating an electric field between the first andsecond electrodes to drive the medicament towards the skin of thepatient.

The system may comprise a heating element and the method may compriseusing the heating element to heat the skin of the patient.

The method may comprise delivering a chemical penetration enhancer intothe skin of the patient. The method may comprise mixing the chemicalpenetration enhancer to the medicament prior to the medicament deliveryinto the skin of the patient.

The method may comprise controlling delivery of the medicament to thepatients skin by a controller.

The method may comprise the use of a wireless communication unitprovided in the device transmitting and/or receiving informationrepresentative of the medicament and/or dose to be administered.

The method may comprise the controller controlling operation of themedicament delivery device dependent on the information received by thewireless communication unit.

The transdermal medicament delivery device may provide a less painful,non-invasive medicament delivery that may be more easily carried out bythe patients themselves. The medicament delivery device may also reduceirritation when delivering medicament for long periods of time. Further,the transdermal medicament delivery device may reduce tissue damage andimprove transport.

The terms “drug” or “medicament” which are used interchangeably herein,mean a pharmaceutical formulation that includes at least onepharmaceutically active compound.

The term “medicament delivery device” shall be understood to encompassany type of device, system or apparatus designed to immediately dispensea drug to a human or non-human body (veterinary applications are clearlycontemplated by the present disclosure). By “immediately dispense” ismeant an absence of any necessary intermediate manipulation of the drugby a user between discharge of the drug from the drug delivery deviceand administration to the human or non-human body. Without limitation,typical examples of drug delivery devices may be found in injectiondevices, inhalers, and stomach tube feeding systems. Again withoutlimitation, exemplary injection devices may include, e.g. patch devices,autoinjectors, injection pen devices and spinal injection systems.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments are described with reference to the accompanyingdrawings, in which:

FIG. 1 is a schematic cross-sectional view of a medicament deliverydevice;

FIG. 2 is a block diagram of a part of the medicament delivery device ofFIG. 1 ;

FIG. 3 is a diagram showing a medicament delivery device in wirelessconnection with various devices;

FIG. 4 is a schematic cross-sectional view of a further medicamentdelivery device;

FIG. 5A is a schematic cross-sectional view of a medicament deliverydevice according to an embodiment;

FIG. 5B is a detail of a medicament delivery device according to avariant of the embodiment shown in FIG. 5A;

FIG. 6A is a schematic cross-sectional view of a medicament deliverydevice according to a further embodiment;

FIG. 6B shows a block diagram of the heating system of the medicamentdelivery device of FIG. 6A; and

FIG. 7 is a schematic cross-sectional view of a medicament deliverydevice according to a still further embodiment.

DETAILED DESCRIPTION

Embodiments provide a medicament delivery device comprising at least onemicroneedle for delivering a medicament to a patient, and a systemconfigured to enhance the penetration of the medicament into the skin ofthe patient. Providing such a medicament delivery device may helptowards avoiding the use of an injection needle for delivering themedicament to the patient. Since no injection needle is needed, such amedicament delivery device does not require a needle hole to be createdat the injection site and so can help towards avoiding tissue injury, aswell as helping to reduce pain and discomfort in the medicament deliveryprocess. In addition, irritations and complications that may occur bythe introduction and/or presence of a needle into the skin in aconventional needle injection device may be avoided. Furthermore, thesystem configured to enhance the penetration of the medicament into theskin of the patient may allow the medicament to overcome more easily theskin barrier and to be, therefore, more efficiently administered.

According to some embodiments of the present disclosure, an exemplarydrug delivery device 10, herein simply referred to as stem configurisshown in FIG. 1 .

In the context of this application, the terms “upstream” and“downstream” are used herein in relation to the direction of medicamentflow through the device in normal use. Moreover, the terms “upper”,“lower”ower terms devare used herein in relation to the orientation ofthe device shown in the accompanying drawings.

The drug delivery device, as described herein, may be configured toinject a medicament into a patient. Such a device could be operated by apatient or care-giver, such as a nurse or physician. The device includesa large volume device (“LVD”) or patch pump, configured to adhere to askin of the patient for a period of time (e.g., about 5, 15, 30, 60, 120minutes or longer) to deliver a “large” volume of medicament (typicallyabout 2 ml to about 10 ml or more).

In combination with a specific medicament, the presently describeddevice may also be customized in order to operate within requiredspecifications. For example, the device may be customized to inject amedicament within a certain time period (e.g. about 10 minutes to about60 minutes or longer). Other specifications can include a low or minimallevel of discomfort, or to certain conditions related to human factors,shelf-life, expiry, biocompatibility, environmental considerations, etc.Such variations can arise due to various factors, such as, for example,a drug ranging in viscosity from about 3 cP to about 50 cP.

The delivery devices described herein can also include one or moreautomated functions. For example, the medicament injection can beautomated. Energy for one or more automation steps can be provided byone or more energy sources. Energy sources can include, for example,mechanical, pneumatic, chemical, or electrical energy. For example,mechanical energy sources can include springs, levers, elastomers, orother mechanical mechanisms to store or release energy. One or moreenergy sources can be combined into a single device. Devices can furtherinclude gears, valves, or other mechanisms to convert energy intomovement of one or more components of a device.

The one or more automated functions of the present drug delivery devicemay each be activated via an activation mechanism. Such an activationmechanism can include one or more of a button, a lever or otheractivation component. Activation of an automated function may be aone-step or multi-step process. That is, a user may need to activate oneor more activation components in order to cause the automated function.For example, in a one-step process, a user may depress a button orinteract with a user interface in order to cause injection of amedicament. Other devices may require a multi-step activation of anautomated function.

Referring to FIG. 1 , the device 10 includes a body or housing 11 whichtypically contains a medicament reservoir 12 (cartridge) pre-filled withliquid medicament to be injected, and the components required tofacilitate one or more steps of the delivery process. The device 10 caninclude a cover or lid 11 a which can be removed when the medicamentreservoir 12 (cartridge) needs to be changed or refilled. The device 10can also include a protective cover 13 that can be detachably adhered toa bottom surface of the device 10. Typically, when using the device 10for the first time, a user must remove the protective cover 13 from thehousing 11 before the device 10 can be operated.

The device 10 is intended to be placed on the skin of the patient, e.g.on the abdomen of the patient. The device 10 is preferably a wearabledevice. Such devices are commonly referred to as “patch pumps” or “skinpatches” due to their nature of being worn or affixed to the skin of thepatient. The device 10 comprises a device holding element 14 e.g. in theform of an adhesive tape 14 (or pad) configured to adhere to the skin ofthe patient. The adhesive pad 14 is attached to the bottom side or skinattachment side of the device 10 and covered by the protective cover 13prior to the first use of the device 10. The adhesive pad 14 ensures theadhesion of the device 10 onto the skin so that in use, the device 10does not detach from the skin. Alternatively, the device 10 comprises adevice holding element operating with vacuum to adhere the device 10 tothe skin.

The device 10 includes a medicament receiving element 15 configured toreceive the medicament flowing from the medicament reservoir 12. In theembodiment described herein, the medicament receiving element 15 is inthe form of a porous membrane, e.g. a fleece or absorbant pad 15. Theabsorbant pad 15 allows for a substantially continuous controlleddelivery of the medicament to the patient.

The device 10 further comprises a microneedle assembly including aplurality of microneedles 16 arranged in an array 17. The microneedleassembly is configured to transdermally deliver medicament to thepatient. The array 17 is disposed downstream of the absorbant pad 15,and is configured to deliver to the patient the medicament flowing fromthe absorbant pad 15. The microneedles 16 extend substantiallydownwardly from a structure or support 18. The support 18 may be madefrom a rigid or flexible sheet of metal or plastic. The support 18 isperforated so that medicament can flow through the support 18 towardsthe microneedles 16. It should be understood that the number ofmicroneedles 16 shown in the figures is for illustrative purposes only.The actual number of microneedles 16 used in the device 10 may, forexample, range between around 70 and around 7000 microneedles, dependingon the area of the bottom surface of the device 10. The size and shapeof the microneedles 16 may also vary as desired. For example, themicroneedles 16 may have an overall conical shape, an overall pyramidalshape or a cylindrical portion upon which is positioned a conicalportion having a tip. The microneedles 16 are typically of a lengthsufficient to penetrate the stratum corneum and pass into the epidermis.In certain embodiments, the microneedles 16 have a length rangingbetween around 0,2 and around 3 millimeters. The microneedles 16 help toovercome the skin barrier by creating pores in the skin, therebyenhancing the penetration of the medicament through the skin. Themicroneedles 16 perforate the outer skin layer and ensure that themedicament diffuses in the pores thereby created. The uptake of themedicament through the skin works by diffusion, i.e. the medicamentflows down a gradient of concentration, from the absorbant pad 15towards the skin of the patient. Once absorbed, the medicament istransported into the blood e.g. with the lymph. The medicament uptake bythe body of the patient via microneedles has been shown to be betterthan subcutaneously, e.g. via an hypodermic injection needle, inparticular in the case of insulin.

The device 10 comprises a tube or hose dispatcher or manifold 19 influid communication with the medicament reservoir 12. The manifold 19includes an inlet 19 a connected to the medicament reservoir 12 and adispense outlet 19 b connected to the absorbant pad 15. The manifold 19is arranged such that, in use, medicament flows from the medicamentreservoir 12 through the manifold 19 via the inlet 19 a, and towards theabsorbant pad 15 via the dispense outlet 19 b. The dispense outlet 19 bis disposed upstream of the absorbant pad 15 and is configured such thatmedicament flowing from the manifold 19 is distributed substantiallyuniformly in the absorbant pad 15. For example, and as visible in FIG. 1, the absorbant pad 15 faces the dispense outlet 19 b and the area ofthe absorbant pad 15 is substantially similar to the area of thecross-section of the dispense outlet 19 b.

A pump mechanism 20 is provided to cause the medicament to flow from themedicament reservoir 12 through the manifold 19. The pump mechanism 20includes a motor 21, a thumb screw 22 and a plug or piston 23. In use,the motor 21 rotates the thumb screw 22, which drives the piston 23within the medicament reservoir 12 towards the manifold 19. While drivenby the motor 21, the piston 23 pushes the medicament out of thereservoir 12 through the manifold 19 via the inlet 19 a, and towards theabsorbant pad 15 via the dispense outlet 19 b. The absorbant pad 15allows for a uniform distribution of the medicament and thereforeensures that the medicament is homogeneously distributed on the array17. The medicament flows from the absorbant pad 15 through the array 17of microneedles 16, and diffuses through the skin.

The device 10 further comprises a controller 24 for monitoring and/orcontrolling the operation of the device 10. The controller 24 includesmemories such as a Random Access Memory and/or a Read-Only Memory, and afirmware configured to control the motor 21 such that the flow or amountof medicament delivered can be varied, e.g. so that the medicament ispumped at a rate which enables the skin to absorb the medicament. Thedevice 10 also comprises a power supply 25, a user interface 26 and awireless communication unit 27.

FIG. 2 is a block diagram schematically showing the electroniccomponents of the device 10 of FIG. 1 . The power supply 25 includes adisposable or rechargeable battery 25 a, a power controller 25 b, and asupply contact 25 c. The supply contact 25 c is configured to enable thedevice 10 to be connected to an external power source for powering thedevice 10 or for recharging the battery 25 a. The power supply 25 isconnected to the controller 24 and to the wireless communication unit 27to supply power to each.

The power supply 25 is connected to the motor 21 via a pulse widthmodulation 35 for powering the motor 21. The controller 24 is connectedto the pulse width modulator 35 to control the drive of the motor 21.The controller 24 is also connected to the wireless communication unit27 and with the user interface 26 to control and receive signal inputfrom each. The pump mechanism 20 and/or reservoir 12 comprise an encoder36, such as a linear transducer. The encoder 36 is connected to thecontroller 24 and is configured to send a signal indicative of theposition of the piston 23 to the controller 24. Alternatively, or inaddition, the encoder 36 is a rotational transducer and is configured tosend a signal indicative of the number of rotations of the thumb screw22 to the controller 24. The controller 24 and the pulse widthmodulation 35 are powered by the power supply 25.

The wireless communication unit 27 is configured to transmit and/orreceive information to/from another device in a wireless fashion. Suchtransmission may for instance be based on radio transmission or opticaltransmission. In some embodiments, the wireless communication unit 27 isa Bluetooth transceiver or NFC transceiver. Alternatively, the wirelesscommunication unit 27 may be substituted or complemented by a wired unitconfigured to transmit and/or receive information to/from another devicein a wire-bound fashion, for instance via a cable or fibre connection.When data is transmitted, the units of the data (values) transferred maybe explicitly or implicitly defined. For instance, in case of an insulindose, always International Units (IU) may be used, or otherwise, theused unit may be transferred explicitly, for instance in coded form.

The controller 24 may be programmed to cause a flow of medicamentthrough the manifold 19 towards the skin of the patient based oninstructions from a separate, remote device. As illustrated in FIG. 3 ,the wireless communication unit 27 may be configured to receiveinstructions from a remote device D, such as a smartphone or tabletrunning a specific application. The wireless communication unit 27 isconfigured to deliver the received instructions to the controller 24. Inone embodiment, the remote device D may be in wireless connection with acontinuous blood glucose monitoring (“BGM”) device G and/or with a teststrip-based BGM device S. The test strip-based BGM device S and/or theBGM device G may send data relating to the blood glucose of the patientto the remote device D. The remote device D may then communicate withthe controller 24, via the wireless communication unit 27, to controlthe pump mechanism 20 and thereby the insulin delivery to the patientdepending on e.g. the blood glucose level of the patient. For example, ablood glucose sensor as described in US20040162470A1 may be used.Alternatively, the user interface 26 can be used by the patient X or ahealthcare professional (“HCP”) to directly program the device 10. Inaddition, the healthcare professional HCP, the patient P or a dispensingpharmacy P may be able to upload data relating to the patient'smedicament requirements, to a cloud-based server, and the remote deviceD may be able to communicate with the cloud-based server to retrievesuch information and control the operation of the device 10 accordingly.For example, a healthcare professional may adjust the medicament regimefor a patient X depending on their latest health test or recent BGMresults, and upload such data to the cloud-based server. The pharmacy Pmay be able to upload the specifics of the dispensed medicament to thecloud-based server, such as medicament concentration, advised deliveryrate and/or volume.

As shown in FIG. 1 , the device 10 comprise an upper or reusable part28, and a lower or disposable part 29. In use, the reusable part 28 andthe disposable part 29 are assembled together. The reusable part 28 maybe removably attachable to the disposable part 29, for example when thereusable part 28 is designed to include costly components of the device10. The reusable part 28 is mechanically connected to the disposablepart 29, e.g. the reusable part 28 is clipped to the disposable part 29.The reusable part 28 is further connected to the disposable part 29 atthe manifold 19, which connects the medicament reservoir 12 in thereusable part 28 to the absorbant pad 15 in the disposable part 29. Insuch an embodiment, a fluid coupling 37 may be provided in the manifold19 to fluidly connect first and second sections of the manifoldrespectively disposed in the reusable part 28 and disposable part 29 ofthe device 10. Therefore, when the reusable part 28 and disposable part29 of the device 10 are mechanically connected together as describedabove, the fluid coupling makes a fluid tight connection between thefirst and second sections of the manifold to ensure reliable delivery ofthe medicament from the reservoir 12 to the absorbant pad 15.

This arrangement of the device 10 has the advantage that the pumpmechanism 20 and the array 17 can be worn together, thereby allowing toavoid the use of a separate supporting device for the pump mechanism 20.This arrangement also allows for a better control of the pump mechanism20. In the embodiment shown in FIG. 1 , the reusable part 28 includesthe electronic components of the device 10, the pump mechanism 20 andthe medicament reservoir 12. The disposable part 29 includes theabsorbant pad 15 and the array 17. It should be noted that the inventionis not intended to be limited to this particular type of device andother types of device are intended to fall within the scope of theinvention. For example, as shown in FIG. 4 , in an alternativeembodiment, the pump mechanism 20 and the medicament reservoir 12 couldbe both located in the disposable part 29, and the drive motor 21 may belocated in the reusable part 28. In the embodiment shown in FIG. 4 , thepump mechanism 20 may be in the form of a peristaltic pump or radialpump. In such an embodiment, a mechanical coupling 38 may be providedbetween a drive output from the motor, and a drive input to the pumpmechanism 20. In a further variant, the device 10 could comprise asingle part, which could be either fully disposable or fully reusable.

As shown in FIG. 5A, the device 10 further comprises a system 30 forelectrically enhancing the penetration of the medicament into the skinof the patient. In the embodiment shown in FIG. 5A, the system 30comprises a first electrode or upper electrode 31(anode), a secondelectrode or lower electrode 32 (cathode), and a DC voltage generator 33connected to the upper and lower electrodes 31, 32. The upper and lowerelectrodes 31, 32 are separated by an electrically insulating materialto avoid short circuits. The absorbant pad 15 may play the role of suchinsulating material. Alternatively, for example in an embodiment wherethe absorbant pad 15 is omitted, an electrically insulating perforatedsheet, e.g. in plastic, may be disposed between the upper and lowerelectrodes 31, 32. In a further alternative, the electrical insulationbetween the upper and lower electrodes 31, 32 may be created by means ofa plurality of insulating balls, e.g. in plastic or covered with aplastic material having electrical insulating properties. The system 30is configured to generate between the upper and lower electrodes 31, 32an electric field for driving or accelerating the medicament towards theskin of the patient. Specifically, the system 30 is configured togenerate between the upper and lower electrodes 31, 32 pulses ofelectric current between the upper and lower electrodes 31, 32 fordriving or accelerating the medicament towards the skin of the patient.

The upper and lower electrodes 31, 32 are in the form of parallelmetallic plates disposed substantially parallel to each other to form acapacitor. The upper and lower electrodes 31, 32 are respectivelydisposed upstream and downstream of the absorbant pad 15. Alternatively,as shown in FIG. 5B, the upper and lower electrodes 31, 32 are disposedupstream of the absorbant pad 15. For example, the upper and lowerelectrodes 31, 32 are disposed in the dispense outlet 19 b.The upperand/or lower electrodes 31, 32 are permeable such that, in use,medicament flows through the upper and/or lower electrodes 31, 32towards the absorbant pad 15. For example, the upper and/or lowerelectrodes 31, 32 are in the form of a perforated plate or hole mask.

The DC voltage generator 33 is configured to generate a voltagedifference between the upper and lower electrodes 31, 32. In theembodiment shown in FIG. 5A, the DC voltage generator 33 is located inthe disposable part 29 of the device 10. However, the DC voltagegenerator 33 could be located at a different location in the device 10,e.g. in the reusable part 28.

The upper electrode 31 and the lower electrode 32 are arranged relativeto each other such that the strength of the electric field between theupper and lower electrodes 31, 32 is optimised. The relation between theelectric field generated and the distance between the upper and lowerelectrodes 31, 32 is defined as follows

$E = \frac{V}{d}$

where E is the electric field, V is the voltage differential between theupper and lower electrodes 31, 32, and d is the distance between theupper and lower electrodes 31, 32. Therefore, it is desirable to have adistance d between the upper and lower electrodes 31, 32 as small aspossible in order to generate an electric field having a strength ashigh as possible.

The system 30 is configured to generate high voltage and short durationpulses between the upper electrode 31 and the lower electrode 32. Thevoltage differential between the upper and lower electrodes 31, 32preferably ranges around 50 volts. The duration of the pulses ispreferably around one or more seconds.

In use, the medicament flows from the reservoir 12 into the manifold 19,towards the dispense outlet 19 b and between the upper and lowerelectrodes 31, 32. The medicament flows between the upper and lowerelectrodes 31, 32 e.g. by means of a capillary force. The pulsedelectric field generated between the upper and lower electrodes 31, 32accelerates molecules in the medicament, e.g. insulin molecules in thecase where the device 10 is an insulin delivery device, or moregenerally polar molecules that are present in the medicament, towardsthe lower electrode 32 and towards the skin of the patient. Thisprocess, also known as electroporation, ensures that the medicament isoptimally transported through the skin of the patient. As shown in FIG.5B, the electric field generated between the upper and lower electrodes31, 32 ionizes the molecules of air present between the upper and lowerelectrodes 31, 32. The ions generated are accelerated by the electricfield towards the lower electrode 32. The ions allows to further openthe skin pores, thereby further enhancing penetration of medicamentthrough the skin. Ventilation means such as a fan could be provided inthe device 10 to further accelerate the medicament towards thepatient'skin.

The high voltage, short duration pulses applied to the skin of thepatient allow to effectively enhance skin penetration of molecules andwater based compounds of the medicament into the skin. For example, thenumber of transdermal pathways available via electroporation is over 500times more than the number of transdermal pathways available viaiontophoresis. The pulsed electric field generated creates pathways inlipid bilayer membranes of the skin, thereby making the penetration ofthe medicament through the skin easier. The device 10 therefore allowsto increase the permeability of the skin of the patient. Specifically,the device 10 allows to transport through the skin a higher volume ofmedicament than a conventional transdermal medicament delivery device.The system 30 also allows to transport through the skin molecules ofhigher molecular weight than with a conventional transdermal medicamentdelivery device. In particular, the combination of the system 30 and thearray 17 of microneedles 16 allows to overcome more easily the skinbarrier and therefore to administer the medicament more efficiently thanwith a conventional medicament delivery device.

A medicament injection device 110 according to a further embodiment isshown in FIG. 6A. The further embodiment corresponds closely to thefirst embodiment and like reference numerals have been used for likecomponents. Differences in relation to the first embodiment aredescribed below.

The device 110 comprises a heating system 130 for enhancing thepenetration of the medicament through the skin of the patient. In theembodiment shown in FIG. 6A, the heating system 130 comprises a heatingelement 134 configured to heat the skin of the patient. The heatingelement 134 is permeable such that, in use, medicament flows through theheating element 134 towards the skin of the patient. For example, theheating element 134 is in the form of a perforated foil. In a variant,the heating element 134 is in the form of a coiled resistance. Theheating element 134 is preferably electrically insulated. The heatingelement 134 is disposed at the dispense outlet 19 b, upstream of theabsorbant pad 15. The heating element 134 is disposed parallel to theabsorbant pad 15. Preferably, the heating element 134 extends along adistance greater than half of the length of the absorbant pad 15, sothat the absorbant pad 15 is efficiently and uniformly heated.

The system 130 comprises a heat controller 135 for controlling thetemperature of the heating element 134. The heat controller 135comprises a temperature sensor. The temperature sensor is for example inthe form of a NTC thermistor, a PTC thermistor, a semiconductor or athermocouple working with the Seebeck effect.

In use, the heating system 130 heats the medicament as well as theinjection site. The heating allows to increase the blood flow in thebody of the patient, proximate the injection site, which enhances themedicament diffusion process. The heating allows to enhancemicrocirculation in the area of the injection site, thus facilitatingmedicament transfer into the body of the patient.

In use, the temperature of the heating element 134 should besufficiently high for enhancing efficiently the medicament diffusionprocess. However, the temperature should not be too high to avoidsweating of the skin, which could decrease the efficiency of themedicament absorption and cause detachment of the device 110 from theskin. In use, the temperature of the heating element 134 is preferablyaround five degrees higher than the temperature of the skin of thepatient. A temperature sensor may be provided in the device 110 tomaintain the heating element 134 at such temperature. Alternatively, asensor may be provided in the device 110 to measure the temperature ofthe room in which the medicament delivery is performed, such that thetemperature of the heating element 134 is maintained at a higher valuethan the temperature of the room, e.g. around five degrees higher thanthe temperature of the room.

A medicament injection device 210 according to a further embodiment isshown in FIG. 7 . The further embodiment corresponds closely to thefirst embodiment and like reference numerals have been used for likecomponents. Differences in relation to the first embodiment aredescribed below.

The device 210 comprises a system 230 for chemically enhancing thepenetration of the medicament into the skin of the patient. In theembodiment shown in FIG. 7 , the system 230 is configured to deliver asupport agent or pore opener or chemical penetration enhancer to thepatient. As shown in FIG. 7 , the system 230 comprises a mechanism formixing the chemical penetration enhancer to the medicament prior to themedicament delivery into the skin of the patient. The mechanismcomprises a reservoir 236 for storing the chemical penetration enhancerand a pump 237 for pumping the chemical penetration enhancer into themanifold 19 where the chemical penetration enhancer contacts themedicament.

The chemical penetration enhancer is, for example, Dimethyl sulfoxide(DMSO). Mixing the medicament with DMSO allows to efficiently improvethe medicament absorption through the skin. In a variant, alcohol suchas ethanol can be added to the medicament prior to the medicamentdelivery. In a further variant, a solution may be added to themedicament to lower the pH value of the medicament such that themedicament has a pH lower than the pH of the skin of the patient. Forexample, a saline solution may be used. The resulting pH gradientbetween the medicament and the skin results in a chemical force whichdrives the medicament through the skin and ensures that the medicamentis efficiently absorbed. In further alternatives, other substances, suchas a fat substance, or urea, can also be added to the medicament tochemically increase the permeability of the skin. The chemicalpenetration enhancer is chosen depending on the medicament to bedelivered.

In one embodiment, the medicament is mixed with an agent to ensure thatthe salt concentration in the skin of the patient and body is greaterthan the salt concentration in the liquid medicament, so that theosmotic pressure created by the gradient of salt concentration betweenthe skin of the patient and the medicament draws the medicament towardsthe skin of the patient.

Alternatively, or additionally, the chemical penetration enhancer may beprovided at the bottom surface or skin attachment side of the device210. The bottom surface may for example comprise a layer of chemicalpenetration enhancer. In one embodiment, the bottom surface includes alayer of water-based substance. Increasing the amount of water at theskin surface allows to moisturize the skin surface and to consequentlyopen skin pores at the injection site, thereby enhancing thepermeability of the skin. Alternatively, a layer of oil-based substancemay be provided at the bottom surface of the device 210.

The terms “drug” or “medicament” are used synonymously herein anddescribe a pharmaceutical formulation containing one or more activepharmaceutical ingredients or pharmaceutically acceptable salts orsolvates thereof, and optionally a pharmaceutically acceptable carrier.An active pharmaceutical ingredient (“API”), in the broadest terms, is achemical structure that has a biological effect on humans or animals. Inpharmacology, a drug or medicament is used in the treatment, cure,prevention, or diagnosis of disease or used to otherwise enhancephysical or mental well-being. A drug or medicament may be used for alimited duration, or on a regular basis for chronic disorders.

As described below, a drug or medicament can include at least one API,or combinations thereof, in various types of formulations, for thetreatment of one or more diseases. Examples of API may include smallmolecules having a molecular weight of 500 Da or less; polypeptides,peptides and proteins (e.g., hormones, growth factors, antibodies,antibody fragments, and enzymes); carbohydrates and polysaccharides; andnucleic acids, double or single stranded DNA (including naked and cDNA),RNA, antisense nucleic acids such as antisense DNA and RNA, smallinterfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleicacids may be incorporated into molecular delivery systems such asvectors, plasmids, or liposomes. Mixtures of one or more drugs are alsocontemplated.

The term “drug delivery device” shall encompass any type of device orsystem configured to dispense a drug or medicament into a human oranimal body. Without limitation, a drug delivery device may be aninjection device (e.g., pen injector, auto injector, large-volumedevice, pump, perfusion system, or other device configured forintraocular, subcutaneous, intramuscular, or intravascular delivery),skin patch (e.g., osmotic, chemical), inhaler (e.g., nasal orpulmonary), an implantable device (e.g., drug- or API-coated stent,capsule), or a feeding system for the gastro-intestinal tract.

The drug or medicament may be contained in a primary package or “drugcontainer” adapted for use with a drug delivery device. The drugcontainer may be, e.g., a cartridge, reservoir, or other solid orflexible vessel configured to provide a suitable chamber for storage(e.g., short- or long-term storage) of one or more drugs. For example,in some instances, the chamber may be designed to store a drug for atleast one day (e.g., 1 to at least 30 days). In some instances, thechamber may be designed to store a drug for about 1 month to about 2years. Storage may occur at room temperature (e.g., about 20° C.), orrefrigerated temperatures (e.g., from about −4° C. to about 4° C.). Insome instances, the drug container may be or may include a dual-chambercartridge configured to store two or more components of thepharmaceutical formulation to-be-administered (e.g., an API and adiluent, or two different drugs) separately, one in each chamber. Insuch instances, the two chambers of the dual-chamber cartridge may beconfigured to allow mixing between the two or more components prior toand/or during dispensing into the human or animal body. For example, thetwo chambers may be configured such that they are in fluid communicationwith each other (e.g., by way of a conduit between the two chambers) andallow mixing of the two components when desired by a user prior todispensing. Alternatively or in addition, the two chambers may beconfigured to allow mixing as the components are being dispensed intothe human or animal body.

The drugs or medicaments contained in the drug delivery devices asdescribed herein can be used for the treatment and/or prophylaxis ofmany different types of medical disorders. Examples of disordersinclude, e.g., diabetes mellitus or complications associated withdiabetes mellitus such as diabetic retinopathy, thromboembolismdisorders such as deep vein or pulmonary thromboembolism. Furtherexamples of disorders are acute coronary syndrome (ACS), angina,myocardial infarction, cancer, macular degeneration, inflammation, hayfever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs anddrugs are those as described in handbooks such as Rote Liste 2014, forexample, without limitation, main groups 12 (anti-diabetic drugs) or 86(oncology drugs), and Merck Index, 15th edition.

Examples of APIs for the treatment and/or prophylaxis of type 1 or type2 diabetes mellitus or complications associated with type 1 or type 2diabetes mellitus include an insulin, e.g., human insulin, or a humaninsulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1analogues or GLP-1 receptor agonists, or an analogue or derivativethereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or apharmaceutically acceptable salt or solvate thereof, or any mixturethereof. As used herein, the terms “analogue” and “derivative” refer toany substance which is sufficiently structurally similar to the originalsubstance so as to have substantially similar functionality or activity(e.g., therapeutic effectiveness). In particular, the term “analogue”refers to a polypeptide which has a molecular structure which formallycan be derived from the structure of a naturally occurring peptide, forexample that of human insulin, by deleting and/or exchanging at leastone amino acid residue occurring in the naturally occurring peptideand/or by adding at least one amino acid residue. The added and/orexchanged amino acid residue can either be codable amino acid residuesor other naturally occurring residues or purely synthetic amino acidresidues. Insulin analogues are also referred to as “insulin receptorligands”. In particular, the term “derivative” refers to a polypeptidewhich has a molecular structure which formally can be derived from thestructure of a naturally occurring peptide, for example that of humaninsulin, in which one or more organic substituent (e.g. a fatty acid) isbound to one or more of the amino acids. Optionally, one or more aminoacids occurring in the naturally occurring peptide may have been deletedand/or replaced by other amino acids, including non-codeable aminoacids, or amino acids, including non-codeable, have been added to thenaturally occurring peptide.

Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) humaninsulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulinglulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28)human insulin (insulin aspart); human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Examples of insulin derivatives are, for example,B29-N-myristoyl-des(B30) human insulin, Lys(B29)(N-tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®);B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin;B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 humaninsulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) humaninsulin, B29-N-omega-carboxypentadecanoyl-gamma-L-glutamyl-des(B30)human insulin (insulin degludec, Tresiba®);B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyhepta-decanoyl) human insulin.

Examples of GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, forexample, Lixisenatide (Lyxumia®, Exenatide (Exendin-4, Byetta®,Bydureon®, a 39 amino acid peptide which is produced by the salivaryglands of the Gila monster), Liraglutide (Victoza®), Semaglutide,Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®),rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3,GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen,Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701,MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864,ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten.

An example of an oligonucleotide is, for example: mipomersen sodium(Kynamro®), a cholesterol-reducing antisense therapeutic for thetreatment of familial hypercholesterolemia.

Examples of DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin,Saxagliptin, Berberine.

Examples of hormones include hypophysis hormones or hypothalamushormones or regulatory active peptides and their antagonists, such asGonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin),Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin,Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

Examples of polysaccharides include a glucosaminoglycane, a hyaluronicacid, a heparin, a low molecular weight heparin or an ultra-lowmolecular weight heparin or a derivative thereof, or a sulphatedpolysaccharide, e.g. a poly-sulphated form of the above-mentionedpolysaccharides, and/or a pharmaceutically acceptable salt thereof. Anexample of a pharmaceutically acceptable salt of a poly-sulphated lowmolecular weight heparin is enoxaparin sodium. An example of ahyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodiumhyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulinmolecule or an antigen-binding portion thereof. Examples ofantigen-binding portions of immunoglobulin molecules include F(ab) andF(ab′)2 fragments, which retain the ability to bind antigens. Theantibody can be polyclonal, monoclonal, recombinant, chimeric,de-immunized or humanized, fully human, non-human, (e.g., murine), orsingle chain antibody. In some embodiments, the antibody has effectorfunction and can fix a complement. In some embodiments, the antibody hasreduced or no ability to bind an Fc receptor. For example, the antibodycan be an isotype or subtype, an antibody fragment or mutant, which doesnot support binding to an Fc receptor, e.g., it has a mutagenized ordeleted Fc receptor binding region. The term antibody also includes anantigen-binding molecule based on tetravalent bispecific tandemimmunoglobulins (TBTI) and/or a dual variable region antibody-likebinding protein having cross-over binding region orientation (CODV).

The terms “fragment” or “antibody fragment” refer to a polypeptidederived from an antibody polypeptide molecule (e.g., an antibody heavyand/or light chain polypeptide) that does not comprise a full-lengthantibody polypeptide, but that still comprises at least a portion of afull-length antibody polypeptide that is capable of binding to anantigen. Antibody fragments can comprise a cleaved portion of a fulllength antibody polypeptide, although the term is not limited to suchcleaved fragments. Antibody fragments that are useful include, forexample, Fab fragments, F(ab′)2 fragments, scFv (single-chain Fv)fragments, linear antibodies, monospecific or multispecific antibodyfragments such as bispecific, trispecific, tetraspecific andmultispecific antibodies (e.g., diabodies, triabodies, tetrabodies),monovalent or multivalent antibody fragments such as bivalent,trivalent, tetravalent and multivalent antibodies, minibodies, chelatingrecombinant antibodies, tribodies or bibodies, intrabodies, nanobodies,small modular immunopharmaceuticals (SMIP), binding-domainimmunoglobulin fusion proteins, camelized antibodies, and VHH containingantibodies. Additional examples of antigen-binding antibody fragmentsare known in the art.

The terms “Complementarity-determining region” or “CDR” refer to shortpolypeptide sequences within the variable region of both heavy and lightchain polypeptides that are primarily responsible for mediating specificantigen recognition. The term “framework region” refers to amino acidsequences within the variable region of both heavy and light chainpolypeptides that are not CDR sequences, and are primarily responsiblefor maintaining correct positioning of the CDR sequences to permitantigen binding. Although the framework regions themselves typically donot directly participate in antigen binding, as is known in the art,certain residues within the framework regions of certain antibodies candirectly participate in antigen binding or can affect the ability of oneor more amino acids in CDRs to interact with antigen.

Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

Pharmaceutically acceptable salts of any API described herein are alsocontemplated for use in a drug or medicament in a drug delivery device.Pharmaceutically acceptable salts are for example acid addition saltsand basic salts.

Those of skill in the art will understand that modifications (additionsand/or removals) of various components of the APIs, formulations,apparatuses, methods, systems and embodiments described herein may bemade without departing from the full scope and spirit, which encompasssuch modifications and any and all equivalents thereof.

1. A method comprising: applying a voltage differential to a firstelectrode of a medicament delivery device and a second electrode of themedicament delivery device to generate an electric field, and flowingmedicament from a reservoir to an array of microneedles arranged on theskin, wherein the electric field increases the flow of medicament. 2.The method of claim 1 further comprising: ionizing molecules of airpresent between the first and second electrode using the electric field,and flowing the ionized molecules of air towards skin of a patient usingthe electric field, such that a permeability of the skin is increased.3. The method of claim 1, wherein applying a voltage differential to afirst electrode of a medicament delivery device and a second electrodeof the medicament delivery device to generate an electric fieldcomprises applying a pulse to the voltage differential to generate apulsing electric field.
 4. A method comprising: applying a heatingelement of a drug delivery device to skin of a patient therebyincreasing a permeability of the skin, wherein the heating element ispermeable, and flowing a medicament through the heating element to theskin of the patient.
 5. The method of claim 4, wherein the heatingelement is disposed upstream of an absorbent pad or parallel to theabsorbent pad.